AChE bivalent inhibitors

PART I. Tacrine- and hupyridone-containing compounds
This page is a continuation of the pages AChE inhibitors and substrates, AChE inhibitors and substrates (Part II), and AChE inhibitors and substrates (Part III).


 * 1zgb Complex with (R)-tacrine-(10)-hupyridone (cmp R-3)
 * 1zgc Complex with (S)-tacrine-(10)-hupyridone (cmp S-3)
 * 1acj Complex with tacrine alone
 * 1h22 Complex with (S,S)-(-)-Bis(12)-hupyridone (cmp (S,S)-(-)-4b)
 * 1h23 Complex with (S,S)-(-)-Bis(10)-hupyridone (cmp (S,S)-(-)-4a)
 * 2cmf Complex with Bis(5)-tacrine derivative (cmp 2d)
 * 2ckm Complex with Bis(7)-tacrine derivative (cmp 2f)
 * 1ut6 Complex with N-9-(1',2',3',4'-TETRAHYDROACRIDINYL)-1,8-DIAMINOOCTANE (cmp 6)
 * 1odc Complex with cmp 7



The active site of TcAChE consists of two binding subsites. First of them is the "catalytic anionic site" (CAS), which involves mentioned above catalytic triad Ser200, His440, and Glu327 (colored orange) and the conserved residues Trp84 and Phe330 also participating in ligands recognition. Another conserved residue Trp279 (colored cyan) is situated at the second binding subsite, termed the "peripheral anionic site" (PAS), ~14 Å from CAS. Therefore, the ligands that will be able to interact with both these subsites, will be more potent AChE inhibitors in comparison to compounds interacting only with CAS. One of the ways to produce such ligands is to introduce two active substances into one compound. If it is spatially necessary these subunits could be divided by alkyl linker with suitable length.

(RS)-(±)-tacrine-(10)-hupyridone
According to the strategy of the use of a bivalent ligand, the inhibitor (RS)-(±)-tacrine-(10)-hupyridone ((R)-3 or (S)-3) was designed and synthesized. It consists of mentioned in the page 'AChE inhibitors and substrates' tacrine (colored magenta), 10-carbon linker (yellow) , and hupyridone (red). The tacrine moiety of this inhibitor binds at the CAS, the linker spans the active-site gorge, and the hupyridone moiety binds at the PAS. The comparison of the (R)-3/TcAChE and tacrine/TcAChE complexes at the <scene name='1zgb/Align/2'>active site. A <scene name='1zgb/Align/7'>comparison of the trigonal (R)-3/TcAChE structure (1zgb; <font color='cyan'>(R)-3 colored cyan ; TcAChE residues interacting with (R)-3 are colored sea-green) with the crystal structure of tacrine/TcAChE (1acj, <font color='magenta'>tacrine colored magenta ; residues interacting with tacrine are colored <font color='pink'>pink ) reveals a similar binding mode for the tacrine moiety. In both structures the tacrine ring is situated at the CAS, between the aromatic residues Trp84 and Phe330. Steric clash with the 10-carbon linker could explain the tilt observed for the Phe330 <font color='yellow'> (yellow and transparent in the tacrine/TcAChE). <font color='red'>Water molecules are shown as red spheres. The tacrine unit of (R)-3 N forms <scene name='1zgb/Align/8'>hydrogen bond with His440 O (3.0 Å) similar to that of tacrine alone. Similarly to the tacrine/TcAChE structure the <font color='red'>system of three water molecules at the CAS ((R)-3/TcAChE) binds the tacrine-linker N via hydrogen bonds to Ser81 O, Ser122 Oγ, and Asn85 Oδ1 (2.6-3.5 Å). The <scene name='1zgc/Al/5'>overlap of <font color='cyan'>(R)-3 (cyan) and <font color='orange'>(S)-3 (1zgc) bound to the TcAChE active site in the orthorhombic forms is shown. <scene name='1zgc/Zgc_h22/2'>Superposition of <font color='magenta'>(S,S)-(-)-4a (magenta) and <font color='orange'>(S)-3 (orange, orthorhombic TcAChE) demonstrates the similar mode of binding of the hupyridone unit at the PAS. The residues Trp279 (top) and Trp84 (bottom) represent the PAS and the CAS, respectively.

Bis-hupyridone
The comparison of the (R)-3/TcAChE (1zgb) and bis-hupyridone/TcAChE complexes (1h22 and 1h23) at the <scene name='1zgb/Align2/2'>active site. <scene name='1zgb/Align2/8'>Superposition of the <font color='cyan'>(R)-tacrine-(10)-hupyridone ((R)-3, cyan) and <font color='orange'>(S,S)-(-)-Bis(12)-hupyridone ((S,S)-(-)-4b, orange, i.e. 12-carbon-tether-linked hupyridone dimer) and <font color='plum'>(S,S)-(-)-Bis(10)-hupyridone ((S,S)-(-)-4a, plum) complexes demonstrates the binding mode of the hupyridone moiety. <font color='magenta'>TcAChE residues of symmetry-related molecule are shown in magenta. X-ray structures of TcAChE complexed with these 10- and 12-carbon-tether-linked 2 <scene name='1zgb/Align2/9'>dimers <font color='plum'>(S,S)-(-)-4a and <font color='orange'>(S,S)-(-)-4b show one subunit bound at the <scene name='1zgb/Align2/10'>CAS, the linker spanning the gorge, and the other subunit bound at the <scene name='1zgb/Align2/11'>PAS. There are two <scene name='1zgb/Align2/12'>hydrogen bonds connecting the <font color='cyan'>hupyridone <font color='red'>O to <font color='magenta'>Lys11 <font color='blue'>Nζ and <font color='cyan'>hupyridone <font color='blue'>N to <font color='magenta'>Gln185 <font color='red'>Oε1 of a <font color='magenta'>symmetry-related molecule at <font color='cyan'>(R)-3 /TcAChE complex. <font color='red'>Water molecules are shown as red spheres. Another hydrogen bond connects the <font color='cyan'>hupyridone <font color='red'>O to a water molecule, which is bound to Ser286 N. Similarly, the hupyridone-PAS unit of both <font color='plum'>(-)-4a and <font color='orange'>(-)-4b forms direct and an indirect hydrogen bonds with the protein backbone in the PAS region.

Bis(n)-tacrine derivatives
<font color='magenta'>2d and <font color='orange'>2f are bis(n)-tacrine derivatives with n=5 and 7 (number of carbons in the linkers), respectively. These compounds are more potent and selective AChE inhibitors than tacrine alone. The binding of the tacrine moiety of <scene name='2cmf/Comparison/2'>2d at the TcAChE catalytic anionic site (CAS) is similar to that of <font color='red'>tacrine  in the tacrine/TcAChE complex (1acj). The second tacrine moiety of the <font color='magenta'>2d interacts with the peripheral anionic site (PAS) near Trp279. The interaction of <font color='magenta'>2d at the CAS causes an increase of the <scene name='2cmf/Comparison/3'>distance between Ser200 Oγ and H440 Nε2 atoms, and, therefore, disruption of the catalytic triad (Ser200, H220, E327) as seen in the <font color='cyan'>native structure (2ace). The binding of 2d results in <scene name='2cmf/Comparison/4'>major structural changes in the Val281-Ser291 loop changing the surface of the active-site gorge from its   <font color='cyan'>native conformation (2ace). The tacrine moiety of the compound <font color='orange'>2f (heptylene-linked bis-tacrine at the CAS, 2ckm) adopts similar <scene name='2cmf/Comparison/5'>conformation as tacrine in the tacrine/TcAChE complex and the tacrine moiety of the <font color='magenta'>2d at the CAS. The second tacrine moiety of the <font color='orange'>2f interacts with PAS near the Trp279, like <font color='magenta'>2d. The <scene name='2cmf/Comparison/6'>binding of <font color='orange'>2f does not cause significant structural changes in <font color='plum'>TcAChE from its <font color='cyan'>native  structure. <scene name='2cmf/Overlap/7'>Comparison of the structures of <font color='magenta'>2d /TcAChE and <font color='orange'>2f /TcAChE reveals different contacts between the tacrine moieties of these compounds at the PAS and  TcAChE. There are two additional structures of tacrine-containing TcAChE complexes: compounds <scene name='2cmf/Comparison/8'>6 (1ut6) and <scene name='2cmf/Comparison/9'>7 (1odc). The tacrine moieties of these compounds adopt similar conformations and interactions with CAS as the tacrine in the tacrine/TcAChE, <font color='orange'>2f /TcAChE and <font color='magenta'>2d /TcAChE. Inhibitors 6 and 7 are spanning the <scene name='2cmf/Comparison/10'>active-site gorge between the CAS and the PAS, but since compound 7 lacks the second tacrine moiety, Trp279 adopts a different conformation in this complex structure. In the three structures: native TcAChE (cyan), cmp 6/TcAChE complex (white), and cmp 7/TcAChE complex (crimson), all the TcAChE active-site gorge residues have identical conformation except Trp279.

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Additional Resources
For additional information, see: Alzheimer's Disease

For information about additional AChE inhibitors see page AChE bivalent inhibitors (Part II).